Recurrence and
metastasis are the main causes of
breast cancer (BRCA)-related death and remain a challenge for treatment. In-depth research on the molecular mechanisms underlying BRCA progression has been an important basis for developing precise
biomarkers and
therapy targets for early prediction and treatment of progressed BRCA. Herein, we identified FERM domain-containing
protein 3 (FRMD3) as a novel potent BRCA
tumor suppressor which is significantly downregulated in BRCA clinical tissue and cell lines, and low FRMD3 expression has been closely associated with progressive BRCA and shortened survival time in BRCA patients. Overexpression and knockdown experiments have revealed that FRMD3 significantly inhibits BRCA cell proliferation, migration, and invasion in vitro and suppresses BRCA xenograft growth and
metastasis in vivo as well. Mechanistically, FRMD3 can interact with
vimentin and
ubiquitin protein ligase E3A(UBE3A) to induce the
polyubiquitin-mediated proteasomal degradation of
vimentin, which subsequently downregulates focal adhesion complex
proteins and pro-cancerous signaling activation, thereby resulting in cytoskeletal rearrangement and defects in cell morphology and focal adhesion. Further evidence has confirmed that FRMD3-mediated
vimentin degradation accounts for the anti-proliferation and anti-
metastasis effects of FRMD3 on BRCA. Moreover, the N-terminal
ubiquitin-like domain of FRMD3 has been identified as responsible for FRMD3-vimentin interaction through binding the head domain of
vimentin and the truncated FRMD3 with the deletion of
ubiquitin-like domain almost completely loses the anti-BRCA effects. Taken together, our study indicates significant potential for the use of FRMD3 as a novel prognosis
biomarker and a therapeutic target of BRCA and provides an additional mechanism underlying the degradation of
vimentin and BRCA progression.